Manufacture of thiolactones

ABSTRACT

The present invention relates to a process for the manufacture of cyclic thio esters (thiolactones) and related compounds by hydrogenation of cyclic thioanhydrides in the presence of metal catalysts.

This application is the US national phase of international applicationPCT/EP2006/003375 filed 12 Apr. 2006 which designated the U.S. andclaims benefit of EP 05008254.4, dated 15 Apr. 2005, the entire contentof which is hereby incorporated by reference.

The present invention relates to a process for the manufacture of cyclic(thiolactones) and related compounds by hydrogenation of cyclicthioanhydrides in the presence of metal catalysts. The products of thisprocess are useful as pharmaceutical or vitamin-type active substances,or as intermediates for the manufacture of such active substances.

By the application of the inventive process, in which the startingmaterials may be prochiral cyclic thioanhydrides, the so manufacturedthiolactones have been found to feature surprisingly high chemo- andenantioselectivities and to be obtained in surprising high chemical andoptical yields.

The invention relates to a process for the manufacture of a thio-lactoneof the general formula

or a hydroxythiolactone or isomers thereof of for example the generalformulas I′ or I′″

or the ring-opened hydroxythiolactone or isomers thereof such as thegeneral formulas I″, I″″, I′″″

wherein each of R¹ and R², independently, signifies —NR⁴R⁵

-   -   and R⁴ and R⁵, each independently, signify hydrogen, substituted        or unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, optionally aromatically substituted        arylalkyl, optionally aromatically substituted arylalkenyl,        cycloalkylalkyl substituted or unsubstituted on the cycloalkyl        moiety, heterocyclyl, substituted or unsubstituted alkanoyl,        substituted or unsubstituted aroyl, substituted or unsubstituted        alkylsulphonyl, substituted or unsubstituted arylsulphonyl or a        silyl group Si(alkyl)₃, Si(aryl)₃ or        Si(alkyl)_(1 or 2)(aryl)_(2 or 1),    -   or the two symbols R⁴ alternatively form together a carbonyl        group and the two remaining symbols R⁵, each independently, have        one of the above-mentioned significances stated for R⁴ and R⁵,        characterized by hydrogenating a cyclic thioanhydride of the        general formula

wherein R¹ and R² have the significances given above,in the presence of a group VIII metal catalyst.

In alternative processes R¹ and R², independently, can signify a group(a) or (b)—OR³  (a)—NR⁴R⁵  (b)

R³ has the meaning of R⁴ and R⁵.

In the above definition of the various significances for R³, R⁴ and R⁵any alkyl embraces straight-chain or (in the case of 3 or more carbonatoms) branched alkyl groups, preferably with up to 12 carbon atoms,more preferably with up to 6 carbon atoms, such as methyl, ethyl,isopropyl, tert. butyl, neopentyl and n-hexyl. This applies equally tothe alkyl part of such substituted or unsubstituted groups as thearylalkyl, cycloalkylalkyl, alkanoyl and alkylsulphonyl groups and toalkyl of the silyl group Si(alkyl)₃ orSi(alkyl)_(1 or 2)(aryl)_(2 or 1). Any alkenyl, as such or as part of ansubstituted or unsubstituted arylalkenyl group, embraces straight-chainor branched alkenyl groups, suitably with up to 12 carbon atoms, morepreferably up to 6 carbon atoms, featuring and depending on the numberof carbon atoms up to three double bonds, preferably one double bond. Anexample of an alkenyl group is allyl. Any cycloalkyl, as such or as partof an substituted or unsubstituted cycloalkylalkyl group, suitablycontains from 3 to 8 carbon atoms, preferably from 4 to 7 carbon atoms.Any aryl, as such or as part of an substituted or unsubstitutedarylalkyl, arylalkenyl, aroyl or arylsulphonyl group, and of the silylgroup Si(aryl)₃ or Si(alkyl)_(1 or 2)(aryl)_(2 or 1), is suitablyphenyl, 1-naphthyl or 2-naphthyl, preferably phenyl. Any heterocyclylmay be such a group of at least partially saturated nature or ofaromatic (heteroaromatic) nature and featuring as ring heteroatoms atleast one selected from oxygen, sulphur and nitrogen atoms, whereby twoor more of such atoms in the ring may be the same or differentheteroatoms. Examples of such groups are tetrahydrofuranyl,tetrahydrodioxanyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, dihydrofuranyl, dihydrodioxanyl,dihydrothiophenyl, pyrrolyl and pyridyl, and any such groups able tofeature one or more fused benzene rings and/or bear a substituent,particularly an alkyl group, on a secondary ring nitrogen atom.

Suitable substituents for substituted or unsubstituted alkyl, alkenyl,alkanoyl or alkylsulphonyl include one or more substituents selectedfrom C₁₋₄-alkoxy and C₁₋₄-alkylthio, whereby two or more substituents onthe same alkyl or alkenyl may be the same or different. In the case ofalkoxyalkyl, this is preferably alkoxymethyl optionally bearing one ortwo alkyl substituents on the methylene moiety. Suitable substituentsfor substituted or unsubstituted cycloalkyl include one or more, same ordifferent, C₁₋₄-alkyl. Suitable substituents for substituted orunsubstituted aryl include are C₁₋₄-alkyl and C₁₋₄-alkoxy, whereby inthis case, too, two or more substituents may be the same or different.This information on the kinds of substituents which come into questionequally applies to the cycloalkyl and aryl moieties when part ofoptionally aromatically substituted arylalkyl, optionally aromaticallysubstituted arylalkenyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted aroyl and substituted or unsubstitutedarylsulphonyl, as appropriate.

In the employed group VIII metal catalyst the group VIII metal (iron,cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium orplatinum) is especially ruthenium (Ru), rhodium (Rh) or iridium (Ir).The catalyst can be homogeneous or heterogeneous, chiral or achiral.

The metal catalyst can be the metal itself, the metal together with achiral and/or achiral modifier, or a metal complex in which the metalhas formally a zero or positive oxidation state. The metal complex canbe free or immobilized on a suitable support, such as active carbon, anorganic polymer, an inorganic or organic ion exchanger or an inorganicmaterial, e.g. silica, titania or alumina. The modifier in the case ofthe metal itself, and the complexing molecule in the case of the metalcomplex catalyst, can be a mono-, bi- or multidentate compound featuringone or more phosphorus, nitrogen, oxygen and/or sulphur atoms which actas the linking sites to the metal atom.

Furthermore, additional organic compounds with metal-complexingproperties and featuring one or more phosphorus, nitrogen and/or sulphuratoms and/or functional groups which can coordinate with the metal maybe present as a part of the catalytic system or an integral part of thecatalytic system. Suitable functional groups include double bonds asoccurring in olefins with one or more double bonds and in aromaticcompounds.

Further constituents of the catalytic system may be inorganic and/ororganic salts and/or protonic acids.

Suitable homogeneous metal complex catalysts are for example of theformula III or IV:[A₁MeYZ]  III[A₁MeY]⁺E₁ ⁻  IVwherein A₁ signifies two tertiary monophosphine ligands or a ditertiarydiphosphine ligand, which together with the metal atom (Me) forms a 5-to 10-membered,preferably 5- to 8-membered, especially a 5- to 7-membered ring,Me signifies noble metal, especially Rh, Ru or Ir,Y signifies two olefines or a diene,Z signifies Cl, Br or I, andE₁ ⁻ signifies the anion of a protonic or complex acid

Suitable olefins Y include a C₂₋₁₂-, preferably a C₂₋₆- and especially aC₂₋₄-olefine, such as propene, 1-butene and (most preferably) ethylene.The diene, being the alternative significance of Y, can contain 5-12,preferably 5-8, carbon atoms, and can be aliphatic, cyclic orpolycyclic. The two double bonds in the diene are preferably separatedby a single or two methylene groups. Examples are 1,3-pentadiene,cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or1,5-heptadiene, 1,4- or 1,5-cycloheptadiene, 1,4- or 1,5-octadiene, 1,4-or 1,5-cyclooctadiene and norbornadiene. Preferably, Y signifies twoethylene or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.

Z in the formula III is preferably Cl or Br. Examples of E₁ ⁻ in theformula IV are ClO₄ ⁻, CF₃SO₃ ⁻, CH₃SO₃ ⁻, HSO₄ ⁻BF₄ ⁻, B(phenyl)₄ ⁻,B(3,5-di(trifluoromethyl)-phenyl)₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsF₆ ⁻ and SbF₆ ⁻.

The tertiary monophosphine ligands, being one of the two significancesfor A₁ in both formulae III and IV, feature bound to one phosphorus atomthree oxygen-bound substituents (phosphites), two oxygen-boundsubstituents and a nitrogen-bound substituent or three carbon-boundsubstituents. The alternative (single) ditertiary diphosphine ligand isone wherein two phosphorus atoms are linked by a bridging group and thephosphorous atoms are bound to the bridging group via oxygen, nitrogenor carbon atoms, and wherein the phosphorus atoms bear two oxygen- orcarbon-bound substituents.

Two oxygen-bound substituents preferably form the residue of a diol, sothat a cyclic phosphonite group is present. The diols are preferably2,2′-dihydroxy-1,1′-diphenyls or -binaphthyls, which can be mono- ormultiply substituted, especially at the 6- and/or 6′-positions forexample with C₁₋₈-alkyl, C₅₋₈-cycloalkyl, C₅₋₈-cycloalkyl-C₁₋₄-alkyl,C₆₋₁₀-aryl, C₇₋₁₂-aralkyl, C₁₋₈-alkoxy, C₅₋₈-cycloalkyloxy,C₅₋₈-cycloalkyl-C₁₋₄-alkoxy, C₆₋₁₀-aryloxy or C₇₋₁₂-aralkyloxy. Examplesare methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, phenyl,benzyl, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, phenyloxy andbenzyloxy.

Tertiary monophosphines and ditertiary diphosphines are well known innumerous examples and described in the literature. Monophosphines anddiphosphines can be chiral, thus promoting the formation of opticalisomers to a large extent when prochiral cyclic dicarboxylic acidanhydrides are hydrogenated in accordance with the process of thepresent invention.

Suitable tertiary monophosphines with three oxygen-bound or twooxygen-bound and a nitrogen-bound substituents are of the formulae V andVI

wherein R₅, R₆, R₇ and R₈, independently, signify a monovalent,unsubstituted or substituted aliphatic, heteroaliphatic, cycloaliphatic,heterocycloaliphatic, cycloaliphatic-aliphatic,heterocycloaliphatic-aliphatic, aromatic, heteroaromatic,aromatic-aliphatic or heteroaromatic-aliphatic groups, R₅ and R₆together form a bivalent, unsubstituted or substituted aliphatic,heteroaliphatic, cycloaliphatic, heterocycloaliphatic,cycloaliphatic-aliphatic-, heterocycloaliphatic-aliphatic, aromatic,heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic group,and R₇ and R₈ together with the nitrogen atom form a 5- or 6-memberedring.

R₅ and R₆ together preferably form a bivalent group, especiallyunsubstituted or substituted 1,1′-binaphth-2,2′-diyl or1,1′-biphen-2,2′-diyl. Examples of the latter are ligands of theformulae

wherein R₇ and R₈ have the significances given above.

Suitable tertiary monophosphines include three C-bound substituentsselected from unsubstituted or substituted aliphatic, heteroaliphatic,cycloaliphatic, heterocycloaliphatic, cycloaliphatic-aliphatic,heterocycloaliphatic-aliphatic, aromatic, heteroaromatic,aromatic-aliphatic and heteroaromatic-aliphatic groups, which suitablycontain up to 18, preferably up to 12, and especially up to 8 carbonand/or heteroatoms, and 4 to 8, preferably 5 to 7, especially 5 or 6ring members. The cyclic groups can be linked, fused or fused and linkedto polycyclic groups, and such ring systems can contain for example 2 to6, preferably 2 to 4, cyclic or heterocyclic carbon atoms.

Heteroatoms or groupings in heterocyclic groups can be selected from—O—, —S—, ═N—, —HN— or —R_(a)N wherein R_(a) preferably signifiesC₁₋₈-alkyl, C₅₋₈-cycloalkyl, C₅₋₈-cycloalkyl-C₁₋₄-alkyl, C₆₋₁₀-aryl,C₇₋₁₂-aralkyl or C₁₋₈-acyl, The aliphatic or heteroaliphatic groups canbe for example straight-chain or branched C₁₋₁₂-alkyl, preferablyC₃₋₈-alkyl, which optionally feature one or more interpolated oxygenand/or sulphur atoms (and thus are for example alkoxyalkyl,alkoxyalkoxyalkyl, alkylthioalkyl, alkylthioalkylthioalkyl etc. groupsor analogous groups featuring both oxygen and thio chain members). Thecycloaliphatic groups are suitably C₅₋₈-cycloalkyl, and theheterocycloaliphatic groups are suitably cyclic groups with 5 to 8 ringmembers including carbon atoms and, as heteroatoms or groupings, one ormore —O—, —S— and/or —NR_(a)— (R_(a) as given above). Thecycloaliphatic-aliphatic groups are suitably C₅₋₈-cycloalkyl-C₁₋₄-alkyl,and the heterocycloaliphatic-aliphatic groups feature theheterocycloaliphatic part of the group as explained above for“heterocycloaliphatic”, and the alkyl part with 1 to 4 carbon atoms. Thearomatic and heteroaromatic groups are suitably C₆₋₁₂-aryl and,respectively, C₅₋₁₁-heteroaryl featuring one or more heteroatoms orgroupings selected from —O—, —S—, ═N—, —HN— and —R_(a)N— (R_(a) as givenabove). In the aromatic-aliphatic or heteroaromatic-aliphatic groups,which are suitably C₆₋₁₂-aryl-C₁₋₄-alkyl or, respectively,C₅₋₁₁-heteroaryl-C₁₋₄-alkyl, the C₅₋₁₁-heteroalkyl part of the lattergroup is as explained above for “C₅₋₁₁-heteroaryl”.

The tertiary monophosphines can also be P-substituted P-cyclic ringswith for example altogether 4-6 ring members (phosphetanes, phospholanesand phosphanes). The P-substituents can be substituted, for example aslater explained for the ditertiary diphosphines. Examples of themonophosphines are trimethylphosphine, tri-tert. butylphosphine,trihexylphosphine, tricyclohexylphosphine, trinorbornylphosphine,triadamantylphosphine, triphenylphosphine, tritoluoylphosphine,trixylylphosphine, phenylphosphoiane and diphenyl-tert. butylphosphine.

The achiral and chiral ditertiary diphosphines include those in whichboth phosphine groups are bound to straight-chain or cyclic linkinghydrocarbon groups at different positions, preferably

-   (a) to different carbon atoms of a C₂₋₆-carbon chain, said chain    being part of a monocyclic ring or part of a bicyclic ring system,    as for example biphenyl or binaphthyl, or cyclopentadienyl-phenyl,    cyclopentadienyl-CH₂-phenyl or cyclopentadienyl-CH(OCH₃)-phenyl in    ferrocenes, or-   (b) to in each case a cyclopentadienyl ring of an substituted or    unsubstituted ferrocene.

The ditertiary of diphosphine ligands contain two secondary phosphinegroups X₁ and X₂, which can contain two identical or differenthydrocarbon groups, preferably two identical hydrocarbon groups.Moreover, the secondary phosphine groups X₁ and X₂ can be the same ordifferent.

The hydrocarbon groups can be unsubstituted or substituted and/orcontain heteroatoms selected from O, S or N. They can contain 1 to 22,preferably 1 to 12, and especially 1 to 8 carbon atoms. A preferredsecondary phosphine is one wherein the phosphine group contains two sameor different groups selected from straight-chain or branchedC₁₋₁₂-alkyl; unsubstituted C₅₋₁₂-cycloalkyl or C₅₋₁₂-cycloalkylmethyl orthis groups substituted with C₁₋₆-alkyl or C₁₋₆-alkoxy; phenyl,naphthyl, furyl or benzyl; or phenyl or benzyl substituted (in the caseof benzyl, on the aromatic ring) with halogen (particularly F, Cl orBr), C₁₋₆-alkyl, C₁₋₆-haloalkyl (e.g. trifluoromethyl), C₁₋₆-alkoxy,C₁₋₆-haloalkoxy (e.g. trifluoromethoxy), (C₆H₅)₃Si, (C₁₋₁₂-alkyl)₃Si,dialkylamino or —CO₂—C₁₋₆-alkyl (e.g. —CO₂CH₃).

Examples of the P-substituents being alkyl, which preferably contains 1to 6 carbon atoms, are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert. butyl and the isomers of pentyl and hexyl. Examples ofthe P-substituents being optionally alkyl substituted cycloalkyl arecyclopentyl, cyclohexyl, methyl- and ethylcyclohexyl, anddimethylcyclohexyl. Examples of P-substitutents being alkyl, alkoxy,haloalkyl, haloalkoxy and halogen substituted phenyl and benzyl are o-,m- and p-fluorophenyl, o-, m- and p-chlorophenyl, difluoro- anddichlorophenyl, pentafluorophenyl, methylphenyl, dimethylphenyl,trimethylphenyl, elhylphenyl, methylbenzyl, methoxyphenyl,dimethoxyphenyl, trifluoromethylphenyl, bis-trifluoromethylphenyl,tris-trifluoromethylphenyl, trifluoromethoxyphenyl,bis-trifluoromethoxyphenyl and 3,5-dimethyl-4-methoxyphenyl.

Preferred secondary phosphine groups are those which feature identicalgroups selected from C₁₋₆-alkyl; unsubstituted cyclopentyl orcyclohexyl; cyclopentyl or cyclohexyl substituted with 1 to 3 C₁₋₄-alkyland/or C₁₋₄-alkoxy groups; and phenyl and benzyl, each unsubstituted orsubstituted (in the case of benzyl, aromatically) with 1 to 3C₁₋₄-alkyl, C₁₋₄-alkoxy, fluorine, chlorine, C₁₋₄-fluoroalkyl and/orC₁₋₄-fluoroalkoxy (up to 3 of the same or different substituents).

The secondary phosphino group preferably has the formula —PR⁹R¹⁰,wherein each of R⁹ and R¹⁰, independently of one another, signifies ahydrocarbon group with 1 to 18 carbon atoms and which is unsubstitutedor substituted with halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, (C₁₋₄-alkyl)₂amino, (C₆H₅)₃Si, (C₁₋₁₂-alkyl)₃Si or—CO₂—C₁₋₆-alkyl, and/or heteroatoms O.

Preferably, R⁹ and R¹⁰ are the same groups selected from straight-chainor branched C₁₋₆-alkyl, unsubstituted cyclopentyl or cyclohexyl;cyclopentyl or cyclohexyl substituted with 1 to 3 C₁₋₄-alkyl and/orC₁₋₄-alkoxy groups; furyl; unsubstituted benzyl; benzyl substitutedaromatically with 1 to 3 C₁₋₄-alkyl and/or C₁₋₄-alkoxy groups; or,especially, unsubstituted phenyl or phenyl substituted with 1 to 3groups/atoms selected from the same or different C₁₋₄-alkyl,C₁₋₄-alkoxy, amino, di(C₁₋₆-alkyl)amino, hydroxyl, fluorine, chlorine,C₁₋₄-fluoroalkyl and C₁₋₄-fluoroalkoxy. R⁹ and R¹⁰ most preferablysignify identical groups selected from C₁₋₆-alkyl, cyclopentyl,cyclohexyl, furyl or substituted or unsubstituted phenyl, the optionallypresent substituents being up to three C₁₋₄-alkyl, C₁₋₄-alkoxy andC₁₋₄-fluoroalkyl groups, and, where two or three of such substituentsare present, these being the same or different.

The secondary phosphine groups X₁ and X₂ can be cyclic secondaryphosphino, e.g. with substituted or unsubstituted ring structures

the optionally present substituents being one or more groups selectedfrom hydroxyl, C₁₋₈-alkyl, C₄₋₈-cycloalkyl, C₁₋₆-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkyl, phenyl, C₁₋₄-alkyl- or C₁₋₄-alkoxyphenyl, benzylC₁₋₄-alkyl- or C₁₋₄-alkoxybenzyl, benzyloxy, C₁₋₄-alkyl- orC₁₋₄-alkoxybenzyloxy, and C₁₋₄-alkylidene-dioxy.

The substituents can be present in one or both the α-positions to thephosphorus atom to enable the presence of chiral carbon atoms.Preferably, the substituents in one or both the α-positions areC₁₋₄-alkyl, e.g. methyl, ethyl, n- or iso-propyl; C₁₋₄-alkoxymethyl;benzyl; or C₆₋₁₀-aryloxymethyl.

The optionally present substituents an alternatively be present in thetwo positions β and γ to the phosphorus atom, and in this case thesubstituents may include divalent substituents attached at the β- andγ-positions. Examples of substituents for β- and/or γ-positions areC₁₋₄-alkyl, C₁₋₄-alkoxy, benzyloxy and (divalent substituents)-O—CH₂—O—,—O—CH(C₁₋₄-alkyl)-O— and —O—C(C₁₋₄-alkyl)₂—O—. Preferred suchsubstituents are methyl, ethyl, methoxy, ethoxy, —O—CH(methyl)-O—, and—O—C(methyl)₂—O—.

Further known and suitable phosphine groups are those derived fromcyclic and chiral phospholanes with 7 carbon atoms in the ring, e.g.those of the formulae

in which the aromatic rings can feature one or more substituentsselected from C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₂-alkyl, phenyl,benzyl, benzyloxy and C₁₋₄-alkylidene-dioxy and C₁₋₄-alkylene-dioxy.Information on such cyclic and chiral phospholanes is known from suchpublications as US 2003/0073868 A1 and WO 02/048161.

Depending on the types, positions and the number of substituents thecyclic phosphine groups can be C-chiral, P-chiral or C- and P-chiral.

The cyclic secondary phosphino groups can for example conform to thefollowing formulae, in each of which only one of the possiblediastereoisomers is represented:

wherein R′ or each of R′ and R″, independently, signifies/signifyC₁₋₄-alkyl, e.g. methyl, ethyl, n- or isopropyl; C₁₋₄-alkoxymethyl;benzyl; or C₆₋₁₀-aryloxymethyl. Additionally, in these cases where R′and R″ are bound to the same carbon atom, they can together form C₄- orC₅-alkylene.

In a preferred embodiment, X₁ and X₂ signify the same or differentnon-cyclic secondary phosphine group(s) selected from —P(C₁₋₆-alkyl)₂,—P(C₅₋₈-cycloalkyl)₂, —P(C₇₋₈-bicycloalkyl)₂, —P(o-furyl)₂, —P(C₆H₅)₂,—P[2-(C₁₋₆-alkyl)-C₆H₄]₂, —P[3-(C₁₋₆-alkyl)-C₆H₄]₂,—P[4-(C₁₋₆-alkyl)-C₆H₄]₂, —P[2-(C₁₋₆-alkoxy)-C₆H₄]₂,—P[3-(C₁₋₆-alkoxy)-C₆H₄]₂, —P[4-(C₁₋₆-alkoxy)-C₆H₄]₂,—P[2-trifluoromethyl-C₆H₄]₂, —P[3-trifluoromethyl-C₆H₄]₂,—P[4-trifluoromethyl-C₆H.]₂, —P[3,5-di(trifluoromethyl)-C₆H₃]₂,—P[3,5-di(C₁₋₆-alkyl)-C₆H₃]₂, —P[3,5-di(C₁₋₆-alkoxy)-C₆H₃]₂ and—P[3,5-di(C₁₋₆-alkyl)-4-(C₁₋₆-alkoxy)-C₆H₂]₂, or a cyclic secondaryphosphine group of one of the formulae

which in each case is unsubstituted or mono- or multiply substitutedwith C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₂-alkyl, phenyl, benzyl,benzyloxy or C₁₋₄-alkylidene-dioxy.

Some specific examples of the non-cyclic and cyclic secondary phosphinegroups are —P(CH₃)₂, —P(isoC₃H₇)₂, —P(n-C₄H₉)₂, —P(isoC₄H₉)₂,—P(C₆H₁₁)₂, —P(norbornyl)₂, —P(o-furyl)₂, —P(C₆H₅)₂, P[2-methyl-C₆H₄]₂,P[3-methyl-C₆H₄]₂, —P[4-methyl-C₆H₄]₂, —P[2-methoxy-C₆H₄]₂,—P[3-methoxy-C₆H₄]₂, —P[4-methoxy-C₆H₄]₂, —P[3-trifluoromethyl-C₆H₄]₂,—P[4-trifluoromethyl-C₆H₄]₂, —P[3,5-di(trifluoromethyl)-C₆H₃]₂,—P[3,5-dimethyl-C₆H₃]₂, —P[3,5-dimethoxy-C₆H₃]₂, and—P[3,5-dimethyl-4-methoxy-C₆H₂]₂, and those groups of the formulae

wherein R′ and R″ have the same significances and are each methyl,ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxymethyl, ethoxymethylor benzyloxymethyl.

The ditertiary diphosphines preferably conform to the formulaX₁—R₁₁—X₂  (IX)wherein X₁ and X₂ have the significances given above and R¹¹ signifiesunsubstituted C₂₋₄-alkylene or C₂₋₄-alkylene substituted withC₁₋₆-alkyl, C₁₋₆-alkoxy, C₅- or C₆-cycloalkyl, phenyl, naphthyl orbenzyl; 1,2- or 1,3-cycloalkylene, 1,2- or 1,3-cycloalkenylene, 1,2- or1,3-bicycloalkylene or 1,2 or 1,3-bicycloalkenylene, each with 4 to 10carbon atoms and either unsubstituted or substituted with C₁₋₄-alkyl,phenyl or benzyl; 1,2- or 1,3-cycloalkylene, 1,2- or1,3-cycloalkenylene, 1,2- or 1,3-bicycloalkylene or 1,2- or1,3-bicycloalkenylene, each with 4 to 10 carbon atoms and beingaugmented at its 1- and/or 2-position or at its 3-position with boundmethylene or C₂₋₄-alkylidene; 1,4-butylene substituted at the 2- and3-positions with —O—CR_(b)R_(c)—O— and being either unsubstituted at its1- and/or 4-position or substituted at such position(s) with C₁₋₄-alkyl,phenyl or benzyl, and wherein each of R_(b) and R_(c) independently,signifies hydrogen, C₁₋₄-alkyl, phenyl or benzyl, 3,4- or2,4-pyrrolidinylene or methylene-4-pyrrolidin-4-yl of which in each casethe nitrogen atom is substituted or unsubstituted with C₁₋₁₂-alkyl,phenyl, benzyl, C₁₋₁₂-alkoxycarbonyl, C₁₋₈-acyl orC₁₋₁₂-alkylaminocarbonyl; or 1,2-phenylene, 2-benzylene, 1,2-xylylene,1,8-naphthylene, 1,1′-dinaphthylene or 1,1′-diphenylene, eachunsubstituted or substituted with halogen, hydroxyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, phenyl, benzyl, phenoxy or benzyloxy; or a group of one ofthe following formulae

in which R¹² signifies hydrogen, C₁₋₈-alkyl, C₁₋₄-fluoroalkyl,unsubstituted phenyl or phenyl bearing up to 3 substitutents the same ordifferent, selected from fluorine, chlorine, bromine, C₁₋₄-alkyl,C₁₋₄-alkoxy and fluoromethyl;n signifies 0 or an integer 1 to 4 and R′ or each R′, independently,signifies C₁₋₄-alkyl, C₁₋₄-fluoroalkyl or C₁₋₄-alkoxy;T signifies C₆₋₂₀-arylene or C₃₋₁₆-heteroarylene;the free bond is located in the ortho position to T-cyclopentadienyl;R″ signifies hydrogen, R₀₀₁R₀₀₂R₀₀₃Si—, C₁₋₁₈-acyl substituted withhalogen, hydroxyl, C₁₋₈-alkoxy; R₀₀₄R₀₀₅N— or R₀₀₆—X₀₀₁C(O)—;each of R₀₀₁, R₀₀₂ and R₀₀₃, independently, signifies C₁₋₁₂-alkyl,unsubstituted C₆₋₁₀-aryl or C₇₋₁₂-arylalkyl or such a group substitutedwith C₁₋₄-alkyl or C₁₋₄-alkoxy;each of R₀₀₄ and R₀₀₅, independently, signifies hydrogen, C₁₋₁₂-alkyl,C₃₋₈-cycloalkyl, C₆₋₁₀-aryl or C₇₋₁₂-aralkyl, or R₀₀₄ and R₀₀₅ togetherform trimethylene, tetramethylene, pentamethylene or 3-oxapentylene;R⁰⁰⁶ signifies C₁₋₁₈-alkyl; C₃₋₈-cycloalkyl unsubstituted or substitutedwith C₁₋₄-alkyl or C₁₋₄-alkoxy; C₆₋₁₀-aryl or C₇₋₁₂-aralkyl, andX₀₀₁ signifies —O— or —NH—.

The cyclopentadienyl rings in the above formulae can, each,independently, be substituted, e.g. with C₁₋₄-alkyl. The tertiarlymonophosphine and the ditertiary diphosphines can be used in the form ofracemates or mixtures of diastereoisomers or they can be used inessentially enantiomeric pure form.

A preferred group of achiral and chiral diphosphines are those of theformulae X to XXIX:

wherein R⁴, T, R′, R″, X₁ and X₂ have the significances given above,including the preferred significances,R¹³ and R¹⁴, each independently, signify hydrogen, C₁₋₄-alkyl, phenyl orbenzyl, the latter two groups being unsubstituted or (aromatically)substituted with 1 to 3 C₁₋₄-alkyl and/or C₁₋₄-alkoxy groups,R¹⁵ and R¹⁶, each independently, signify hydrogen, C₁₋₄-alkyl, phenyl orbenzyl,R¹⁷ and R¹⁸, each independently, signify hydrogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, phenyl or benzyl, the latter two groups being unsubstitutedor (aromatically) substituted with 1 to 3 C₁₋₄-alkyl and/or C₁₋₄-alkoxygroups,R¹⁹ signifies hydrogen, C₁₋₁₂-alkyl, phenyl, benzyl, the latter twogroups being unsubstituted or (aromatically) substituted with 1 to 3C₁₋₄-alkyl and/or C₁₋₄-alkoxy groups, C₁₋₁₂-alkoxy-C(O)—, phenyl-C(O)—,benzyl-C(O)—, the latter two groups being unsubstituted or substitutedwith 1 to 3 C₁₋₄-alkyl and/or C₁₋₄-alkoxy groups, C₁₋₁₂-alkyl-NH—CO,phenyl —NH—C(O)— or benzyl-NH—C(O)—, the latter two groups beingunsubstituted or substituted with 1 to 3 C₁₋₄-alkyl and/or C₁₋₄-alkoxygroups,X signifies 0, 1 or 2,R²⁰ and R²¹, each independently, signify C₁₋₄-alkyl or C₁₋₄-alkoxy, orR²⁰ and R²¹ together form oxadimethylene,R²², R²³, R²⁴, R²⁵, R²⁶ and R²⁷ signify, each independently, hydrogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₅- or C₆-cycloalkyl or cycloalkoxy, phenyl,benzyl, phenoxy, benzyloxy, halogen, hydroxyl,—(CH₂)₃—C(O)—O—C₁₋₄-alkyl, —(CH₂)₃—C(O)—N(C₁₋₄-alkyl)₂ or—N(C₁₋₄-alkyl)₂, or R²² and R²⁴, and/or R²⁰ and R²⁴, and/or R²³ and R²⁵,and/or R²¹ and R²⁵, or R²⁴ and R²⁶ and/or R²⁵ and R²⁷ each together forma fused 5- or 6-membered mono- or bicyclic hydrocarbon ring, andR²⁸ signifies hydrogen, C₁₋₆-alkyl, cyclohexyl or phenyl.

Some preferred examples of chiral ditertiary diphosphines are those ofthe following formulae:

wherein R signifies branched C₃₋₈-alkyl, cyclohexyl, norbornyl,adamantly, unsubstituted phenyl or phenyl substituted with 1 to 3C₁₋₄-alkyl, C₁₋₄-alkoxy and/or trifluoromethyl groups, or with amino,(C₁₋₄-alkyl)NH— or (C₁₋₄-alkyl)₂N—,R⁴ signifies hydrogen or C₁₋₄-alkyl,T signifies 1,2-phenylene, R′ hydrogen and R″ C₁₋₄-alkyl,R²⁹ and R³⁰, each independently signify C₁₋₄-alkyl, phenyl or benzyl,most preferably methyl,R³¹ signifies C₁₋₈-alkyl, C₁₋₈-acyl or C₁₋₈-alkoxycarbonyl,R³² signifies hydrogen or, independently, has the significance of R³³,and R³³ signifies C₁₋₄-alkyl, phenyl or benzyl,R³⁴ signifies methyl, methoxy or both R³⁴ together oxadimethylene,R³⁵ and R³⁶, each independently, signifies hydrogen, C₁₋₄-alkyl,C₁₋₄-alkoxy or (C₁₋₄-alkyl)₂N—,R³⁷ and R³⁸, each independently, signify hydrogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, —(CH₂)₃—C(O)—O—C₁₋₄-alkyl or —(CH₂)₃—C(O)—N(C₁₋₄-alkyl)₂,andR³⁹ signifies C₁₋₄-alkyl, most preferably methyl.

Suitable ditertiary diphosphines with heterocyclic structures aredescribed in EP-A-0 770 085, by T. Benincori et al. in J. Organomet.Chem. 529 (1997), pages 445-453 and in J. Org. Chem. 61, page 6244(1996), by F. Bonifacio et al. in Chiratech 1997, 11-13, November 1997,Philadelphia, Pa., USA and by L. F. Tietze et al., Chem. Commun. pages1811-1812 (1999). Some examples are

Suitable ditertiary diphosphines are also described for example inComprehensive Asymmetric Catalysis (E. N. Jacobsen, A. Pfalz and H.Yamamoto (eds.)), Vol. I-III, Springer-Verlag, Berlin, 1999.

Some preferred catalysts include

As the hydrogen source for the hydrogenation there may be used hydrogenitself or a hydrogen donor, such as an aliphatic alcohol, e.g.isopropanol, or ammonium formate.

The process in accordance with the invention can be effected in an inertsolvent, or in the absence of a solvent. Suitable solvents includealiphatic, cycloaliphatic and aromatic hydrocarbons, examples thereofbeing pentane, hexane, petrol esters, cyclohexane, methylcyclohexane,benzene, toluene and xylene; optionally fluorinated alcohols, examplesthereof being methanol, ethanol, propanol, butanol, ethylene glycolmonomethyl ether and diethylene glycol monomethyl and monoethyl ethers(the latter three examples also belonging to the solvent class ethers),and 1,1,1-trifluoroethanol; aliphatic and cyclic ethers, examplesthereof being diethyl ether, dibutyl ether, tert. butyl methyl ether,ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethylene glycol dimethyl ether, tetrahydrofuran, dioxan and diethyleneglycol monomethyl and monoethyl ethers (the latter two examples alsobelonging to the solvent class alcohols); aliphatic ketones, examplesthereof being acetone and methyl isobutyl ketone; aliphatic carboxylicacid, e.g. acetic acid; aliphatic carboxylic acid esters and lactones,e.g. methyl acetate, ethyl acetate and valerolactone; aliphaticcarboxylic acid amides, e.g. N,N-dimethyl acetamide anddimethylformamide; N-substituted lactones, e.g. N-methylpyrrolidone;cyclic ureas, e.g. N,N-dimethyl-imidazolidin-2-one; aliphatic andalicyclic sulphoxides and sulphones, examples thereof being dimethylsulphoxide, dimethyl sulphone, tetramethylene sulphoxide andtetramethylene sulphone; and water. The solvent can be used in theprocess as the sole one, or a mixture of at least two solvents, e.g.taken from the above classes or examples thereof, may be used. Preferredclasses of solvents are the hydrocarbons, the alcohols and the ethers.

The metal or the metal constituent of the metal complex catalyst issuitably used in an amount, relative to the amount of cyclicdicarboxylic acid anhydride starting material, in the range from about0.0001 to about 10 mol %, preferably from about 0.001 to about 10 mol %,and most preferably from about 0.1 to about 5 mol %.

In addition to the employed metal catalyst a co-catalyst can be used inthe process in accordance with the invention. Such a co-catalyst issuitably an alkali metal or substituted or unsubstituted ammonium,particularly quaternary ammonium, halide. The alkali metal isparticularly lithium, sodium or potassium, and the halide particularlybromide or iodide, preferably the latter. In respect of the quaternaryammonium halide, the substituents on ammonium are suitably lower alkyl,especially C₁₋₆-alkyl, groups and/or aryl, especially phenyl, groups. Inthe case where a co-catalyst is used the amount thereof relative to 1equivalent of the employed metal catalyst is suitably from about 0.1 toabout 100 equivalents, preferably from about 10 to about 80 equivalents.

Moreover, as well as with the co-catalyst, the process of the presentinvention may also be carried out in the presence of a protonic acid,for example a mineral acid, a carboxylic acid or a sulphonic acid.Examples of such protonic acids are hydrochloric acid, acetic acid andp-toluenesulphonic acid, respectively. If not simultaneously in the roleof a solvent for the process, the protonic acid is suitably used in anamount from about from about 0.001 weight percent (wt. %) to about 50wt. %, preferably from about 0.1 wt. % to about 50 wt. %.

Literature on the simultaneous employment of co-catalysts and protonicacids includes U.S. Pat. No. 5,371,256, U.S. Pat. No. 5,446,884, U.S.Pat. No. 5,583,241 and EP-A-0 691 949.

The process in accordance with the invention is affected at temperaturesconveniently from about 80° C. to about 200° C., preferably from about100° C. to about 180° C., and most preferably from about 120° C. toabout 170° C. In general the optical yields achieved are higher when thereaction is performed at lower temperatures in these ranges than at thehigher temperatures. On the other hand a more rapid conversion isgenerally achieved at the higher temperatures than at the lowertemperatures.

Moreover, the (hydrogenation) process can be effected under normal orunder an elevated pressure. Typically a pressure in the range from about0.1 MPa to about 150 MPa is employed. In one embodiment of the presentinvention the process is performed under pressure above atmosphericpressure of 1 bar, preferably between 20 to 150 bar, more preferablybetween 20 and 100 bar and most preferably between 50 and 80 bar.

The metal catalyst can be employed in the process in accordance with theinvention as such (preformed), or may be formed in situ in the presenceof the cyclic thioanhydride starting material and other materials, e.g.solvent and co-catalyst, involved in the reaction. It can furthermore beadvantageous in the case of using a preformed catalyst to augment thereaction mixture with ligand(s), or in the case of an in situpreparation of the catalyst to use an excess of ligand(s); such ligandexcess can amount to up to a 6 molar excess, preferably up to 2 molarexcess, based on the molar amount of the employed noble metal catalyst.

Depending on the employed catalyst, reaction conditions and solvent (ifused) either the thiolactone of the formula I or the hydroxythiolactoneof the formula I′ or isomers thereof or the ring-opened hydroxylactoneof the formula I″ or isomers thereof are obtained chemoselectively. Thestereoselectivity with which I, I′ or I″, I′″, I″″, I′″″ are obtainedalso depends on the employed catalyst, reaction conditions and solvent(if used).

In general the process of the present invention can be performedbatchwise or continuously.

The process in accordance with the present invention is preferablyapplied for hydrogenation a cyclic thioanhydride of the general formula

wherein each R⁵, independently, signifies one of the meanings givenabove for R⁴ and R⁵, preferably hydrogen, substituted or unsubstitutedalkenyl, substituted or unsubstituted arylalkyl, heterocyclyl, —COalkyl,—SO₂alkyl, —SO₂aryl or —Si(alkyl)₃, especially allyl, benzyl,p-methoxybenzyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl.in the presence of a metal catalyst to yield the appropriate thiolactoneof the general formula

preferably enantioselectively in an optical purity greater than 50% ee(in the 3aS, 6aR form).

The invention is illustrated by the following Examples.

Experimental Procedure for the Asymmetric Hydrogenation Of“Cyclothioanhydride”

Formula IIa, wherein R⁵═R⁵=benzyl

In a glove box, under an argon atmosphere with exclusion of oxygen, atroom temperature (20-22° C.), a 15-ml stainless steel autoclave withglass insert was filled with starting material thioanhydride IIa (0.50g, 1.412 mmol). In a second flask, [Ir(cod)Cl]₂ (2 mg, 0.00296 mmol) and(S)-(−)-MeOBIPHEP (3.45 mg, 0.00592 mmol) were mixed with 2.5 mltetrahydrofurane (distilled over sodium/benzophenone ketyl/argon) andshaken for 10 min. This solution (ratio ligand:iridium=2:1) was thenplaced into the autoclave containing the anhydride starting material.The ratio substrate/Ir is ca. 500. The autoclave was closed in the glovebox. Then the autoclave was purged with nitrogen (5 bar, 3 times), andthen with hydrogen (10 bars, 3 times), set at 30 bar, the temperaturewas maintained at 150° C., and the autoclave shaken at that temperaturefor 20 hours. Then the autoclave was cooled down to room temperature,and the pressure released. The orange reaction mixture (a clearsolution) was evaporated to dryness under reduced pressure, to yield0.53 g of a brown solid. Conversion and chemoselectivity were determinedby ¹H-NMR and HPLC, the enantiomeric purity of the thiolactone obtainedwas determined by HPLC (Chiralpak AS-H, 250×4.6 mm, solventisopropanol:n-hexane:acetonitrile=62:35:3, detection at 210 nm, t_(R)(D-thiolactone) 34 min, t_(R) (L-thiolactone) 38 min,). Yield ofthiolactone 2.1%, ratio D-thiolactone:L-thiolactone=39.3:60.7(enantiomeric excess 21%).

In another example, starting from 0.05 g thioanhydride IIa, with a ratiosubstrate/Ir of ca. 50, under otherwise identical conditions as given inthe example specified above, the following results were obtained: 0.065g of a brown oil, yield of thiolactone 4%, ratioD-thiolactone:L-thiolactone=41.0:59.0 (enantiomeric excess 18%).

1. A process for the manufacture of a thiolactone of the general formula

or a hydroxythiolactone of the general formula

or the ring-opened hydroxythiolactone of the general formula I″ orisomers thereof

wherein each of R¹ and R², independently, signifies —NR⁴R⁵ and R⁴ andR⁵, each independently, signify hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, optionallyaromatically substituted arylalkyl, optionally aromatically substitutedarylalkenyl, cycloalkylalkyl substituted or unsubstituted on thecycloalkyl moiety, heterocyclyl, substituted or unsubstituted alkanoyl,substituted or unsubstituted aroyl, substituted or unsubstitutedalkylsulphonyl, substituted or unsubstituted arylsulphonyl or a silylgroup Si(alkyl)₃, Si(aryl)₃ or Si(alkyl)_(1 or 2)(aryl)_(2 or 1), or thetwo symbols R⁴ alternatively form together a carbonyl group and the tworemaining symbols R⁵, each independently, have one of the abovementioned significances stated for R4 and R5 wherein the processcomprises hydrogenating a cyclic thioanhydride of the general formula

in the presence of a group VIII metal catalyst.
 2. A process accordingto claim 1, wherein the metal in the metal catalyst is ruthenium,rhodium or iridium.
 3. A process according to claim 1, wherein thecatalyst is homogeneous or heterogeneous, chiral or achiral.
 4. Aprocess according to claim 1, wherein the metal catalyst is the metalitself, the metal together with a chiral and/or achiral modifier, or ametal complex comprising a metal and a complexing molecule wherein themetal has formally a zero or positive oxidation state, the metal complexbeing free or immobilized on a suitable support.
 5. A process accordingto claim 4, wherein the chiral and/or achiral modifier, and/or thecomplexing molecule, is a mono-, bi- or multidentate compound having oneor more phosphorus, nitrogen, oxygen and/or sulphur atoms which act asthe linking sites to the metal atom.
 6. A process according to claim 1,wherein a homogeneous metal complex catalyst is used which is of formulaIII or IV[A₁MeYZ]  III[A₁MeY]⁺E₁ ⁻  IV wherein A₁ signifies two tertiary monophosphine ligandsor a ditertiary diphosphine ligand, which together with the metal atom(Me) forms a 5- to 10-membered ring, Me signifies a noble metal, Ysignifies two olefines or a diene, Z signifies Cl, Br or I, and E₁ ⁻signifies an anion of a protonic or complex acid.
 7. A process accordingto claim 1, wherein the process is effected in an inert solvent,selected from an aliphatic, cycloaliphatic or aromatic hydrocarbon, afluorinated or unfluorinated alcohol, an open aliphatic or cyclicaliphatic ether, an aliphatic ketone, an aliphatic carboxylic acid, acarboxylic acid ester or lactone, an aliphatic carboxylic acid amide, aN-substituted lactone, a cyclic urea, an aliphatic or alicyclicsulphoxide or sulphone, or water, or a mixture of at least two solventstaken from the above classes.
 8. A process according to claim 1, whereinthe metal or the metal constituent of the metal complex catalyst is usedin an amount, relative to the amount of cyclic thioanhydride startingmaterial, in the range from about 0.0001 to about 10 mol %.
 9. A processaccording to claim 1, wherein in addition to the employed metal catalysta co-catalyst is used which is an alkali metal or a substituted orunsubstituted ammonium halide.
 10. A process according to claim 1,wherein the process is carried out in the presence of a protonic acid.11. A process according to claim 1, wherein the process is effected attemperatures from about 80° C. to about 200° C.
 12. A process accordingto claim 1, wherein the cyclic thioanhydride of the general formula

wherein each R⁵, independently, signifies one of the meanings givenabove for R⁴ and R⁵, preferably hydrogen, substituted or unsubstitutedalkenyl, substituted or unsubstituted arylalkyl, heterocyclyl, —COalkyl,—SO₂alkyl, —SO²aryl or —Si(alkyl)₃, especially allyl, benzyl,p-methoxybenzyl, 1-furyl, 2-furyl, 1-thienyl or 2-thienyl, ishydrogenated in the presence of a metal catalyst to yield theappropriate thiolactone of the general formula


13. A process according to claim 1, wherein the pressure is aboveatmospheric pressure of 1 bar.
 14. A process according to claim 2,wherein the metal is iridium.
 15. A process according to claim 6,wherein a 5- to 8-membered ring is formed.
 16. A process according toclaim 6, wherein a 5- to 7-membered ring is formed.
 17. A processaccording to claim 6, wherein the noble metal is Rh, Ru or Ir.
 18. Aprocess according to claim 8, wherein the amount of starting material isfrom about 0.001 to about 10 mol %.
 19. A process according to claim 8,wherein the amount of starting material is from about 0.1 to about 5 mol%.
 20. A process according to claim 9, wherein the co-catalyst is asubstituted or unsubstituted quaternary ammonium halide.
 21. A processaccording to claim 10, wherein the acid is a mineral acid, a carboxylicacid or a sulphonic acid.
 22. A process according to claim 11, whereinthe temperature is from about 100° C. to about 180° C.
 23. A processaccording to claim 11, wherein the temperature is from about 120° C. toabout 170° C.
 24. A process according to claim 13, wherein the pressureis between 20 to 150 bar.
 25. A process according to claim 13, whereinthe pressure is between 20 to 100 bar.
 26. A process according to claim13, wherein the pressure is between 50 to 80 bar.